Discovery of tricyclic 5,6-dihydro-1H-pyridin-2-ones as novel, potent, and orally bioavailable inhibitors of HCV NS5B polymerase

A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-11, Vol.19 (22), p.6404-6412
Main Authors: RUEBSAM, Frank, MURPHY, Douglas E, BLAZEL, Julie K, SUN HEE KIM, YUEFEN ZHOU, QING HAN, KISSINGER, Charles R, WEBBER, Stephen E, SHOWALTER, Richard E, SHAH, Amit M, TSAN, Mei, PATEL, Rupal A, TRAN, Chinh V, THOMPSON, Peggy A, LEBRUN, Laurie A, HOU, Huiying J, KAMRAN, Ruhi, SERGEEVA, Maria V, BARTKOWSKI, Darian M, NOLAN, Thomas G, NORRIS, Daniel A, KHANDURINA, Julia, BROOKS, Jennifer, LI, Lian-Sheng, OKAMOTO, Ellen, KIRKOVSKY, Leo, JINGJING ZHAO, DRAGOVICH, Peter S, MCGUIRE, Helen M, XIANG, Alan X, ZHONGXIANG SUN, AYIDA, Benjamin K
Format: Article
Language:English
Subjects:
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Antiviral Agents - pharmacokinetics
Biological and medical sciences
Biological Availability
Chemistry, Pharmaceutical
Crystallography, X-Ray
Drug Design
Drug Evaluation, Preclinical
Genotype
Hepacivirus - drug effects
Hepatitis C
Hepatitis C virus
Medical sciences
Molecular Structure
Pharmacology. Drug treatments
RNA Replicase
Structure-Activity Relationship
Viral Nonstructural Proteins - antagonists & inhibitors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.09.045